Epidemiology, treatment and outcomes of primary renal sarcomas in adult patients

To assess epidemiology, clinical presentation, treatment and overall survival of adult patients with renal sarcomas, the 2004–2016 SEER and NCDB databases were queried for adult patients diagnosed with renal sarcoma, calculating average annual age-adjusted incidence rates (AAIR) and average annual percentage change (AAPC) as well as overall survival (OS). In n = 1279 included renal sarcoma patients, AAIR remained constant over the study period (average 0.53 cases/1million; AAPC = 0.7, p = 0.6). Leiomyosarcoma (AAIR 0.14 cases/1 million) and malignant rhabdoid tumors (0.06 cases/1 million) were most common. Sarcoma histiotypes demonstrated considerable heterogeneity regarding demographic and cancer-related variables. Patients presented with advanced local extent (T3 33.3%; T4 14.2%) or distant metastases (29.1%) and commonly underwent surgical resection (81.6%). Longer OS was independently associated with younger age, female sex, lower comorbidity index, low T stage, negative surgical margins, absence of tumor necrosis or distant metastases and leiomyosarcoma histiotype (multivariable p < 0.05 each). Treatment efficacy varied according to sarcoma histiotype (interaction p < 0.001). Accounting for 0.25% of renal malignancies, renal sarcomas include 43 histiotypes with distinct epidemiology, clinical presentation, outcomes and sensitivity to systemic therapy, thereby reflecting soft-tissue sarcoma behavior. Renal sarcoma treatment patterns follow recommendations by renal cancer guidelines with surgical resection as the cornerstone of therapy.


Material and methods
Data from the US-based National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) program were evaluated in this study.
The NCDB, which was established in 1989 by the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society as a joint quality improvement project, contains data on more than 34 million cancer patients, which were recorded from over 1,500 CoC-accredited facilities across the United States.It is estimated that approximately 70% of the annually diagnosed US cancer cases are reported in the NCDB 12 .In contrast, the SEER database includes cancer cases from selected population-based state cancer registries in the United States 13 .The SEER 21 database evaluated in this study contains data from 21 cancer registries in 19 geographic areas, allowing analyses which are generalizable to the entire US population.
This study received prior approval by the local institutional review board and is Health Insurance Portability and Accountability Act (HIPAA) compliant.Informed patient consent was waived due to the study´s design evaluating anonymized databases.

Study cohort
The 2019 NCDB participant user file containing cancer cases diagnosed between 2004 and 2016 was queried for adult patients with histopathological diagnosis of invasive (ICD-03 behavior code /3) sarcomas with renal origin (primary site codes C649, C659; ICD-03 codes provided in supplemental Table 1).Exclusion criteria were age < 18 years, missing histopathological assessment, and non-invasive behavior (ICD-03 behavior codes /1 and /2).
Inclusion criteria for the SEER 21 database were age > = 18 years and renal sarcoma diagnosis (as detailed above) between 2004 and 2016 to match the study period to that of the NCDB.

Variables
The SEER 21 database was used for calculation of age-adjusted incidence rates (AAIR), which were standardized to the 2000 US population.All other variables were based on NCDB data.
Renal sarcoma histiotypes were categorized into "tumor groups" according to their cellular origin as summarized in figure appendix Table 1.Further details on NCDB variables evaluated in this study are provided in the supplement.
All treatment variables provided by the NCDB referred to primary treatment of renal sarcomas.Information on therapy for recurrent sarcomas was not provided by the NCDB.

Statistical analyses
Continuous variables were provided as median with inter-quartile range (IQR).Categorical variables were provided as number and frequency.Across patient subgroups, continuous variables were assessed using the nonparametric Wicoxon rank sum test, and categorical data using the chi-square test.
Temporal AAIR trends were visualized using generalized additive models.
Overall survival was assessed weighted Cox regression models with robust variance estimators due to apparent violation of the proportional hazards assumption with crossing Kaplan-Meier curves 14 .Variables were considered for inclusion in the final multivariable model if p < 0.1 in univariate analyses.
Given the variety of sarcoma histiotypes, often containing less than 10 cases, only the 8 most common histiotypes were considered as distinct strata for statistical modelling.
Age-adjusted incidence rates were calculated as annual AAIR or average annual AAIR using the SEER*Stat software.Average annual percentage change (AAPC) of AAIR were assessed using the Jointpoint regression program version 4.8.0.1.
All other statistical analyses were conducted using R version 3.6.0(Vienna, Austria) and RStudio version 1.3.959(RStudio Inc, Boston, MA, USA).A p-value of < 0.05 was defined to indicate statistical significance.All provided p-values are two-sided.

Results
A total n = 609 renal sarcoma cases were included from the SEER 21 database and used for assessment of epidemiological trends.
Another n = 1279 renal sarcoma cases were included from the NCDB database and used for evaluation of clinical presentation, treatment, and outcomes, as detailed below.

Epidemiology
Renal sarcoma diagnosis comprised 0.25% of all SEER-reported renal malignancies between 2004 and 2016.
Renal sarcoma incidence rates further varied according to age at diagnosis, with generally higher incidence rates for older patients (supplemental Fig. 2).
In the NCDB data, clinical presentation of renal sarcomas varied according to the 43 different histiotypes as depicted in Fig. 4 and supplemental Fig.

Renal sarcoma treatment
While surgical resection was generally the cornerstone of renal sarcoma therapy, treatment variability was seen according to tumor stage and metastatic status, as summarized in Table 2 and supplemental Table 2.
For 282 patients, data on sequencing of surgical treatment and systemic therapy was available: in the majority of these patients, systemic therapy was used in an adjuvant setting (n = 263/282; 93.3%), and less commonly in a neoadjuvant (n = 13/282; 4.6%).

Renal sarcoma outcome
Data on survival time and survival status was available for n = 1177 NCDB renal sarcoma patients.In this cohort, median follow-up time was 77.7 months (IQR: 39.8-109 months).
The median OS for all renal sarcomas was 25 months, but OS rates varied according to sarcoma histiotype, as demonstrated in supplemental Table 3.
As detailed in Fig. 5 and supplemental Table 4, OS independently varied with sarcoma histiotype on multivariable analyses: shorter OS was observed in patients with angiosarcomas compared to those with LMS (HR = 2.42, 95% CI 1.89-3.1,p < 0.001).
In multivariable analyses, longer OS was reported in younger female patients with lower T stage, without histological tumor necrosis and distant metastases, as well as patients receiving surgical treatment and systemic therapy (multivariable p < 0.05, each).
Due to statistical collinearity with surgical treatment, the OS effect of surgical margin was separately assessed in surgically resected patients, where renal sarcomas with positive surgical margin independently demonstrated shorter OS versus R0 resected sarcomas (R + vs. R0, HR = 1.36, 95% CI 1.1-1.68,p = 0.004; see supplemental Table 5).

Sarcoma histiotype-specific treatment outcome
On multivariable OS models, a statistically significant interaction between sarcoma treatment and histiotype was evident, indicating varying effectiveness of systemic therapy (interaction p < 0.001) and surgical resection (interaction p < 0.001) according to sarcoma histiotype.Supplemental Fig. 4 details this heterogeneity, demonstrating longer OS for systemic therapy versus none in patients with LMS, angiosarcoma and clear cell sarcoma (p < 0.05, respectively) after multivariable adjustment.
Longer OS for surgical resection versus none was observed in LMS, malignant rhabdoid tumors, PNET, Ewing sarcoma, and spindle cell sarcoma (p < 0.05, respectively).

Discussion
Sarcomas are a heterogenous group of tumors that manifest throughout the body, varying in their clinical presentation, behavior and outcome 5 .
Using the SEER and NCDB databases, we demonstrated that renal sarcomas comprise 0.25% of all renal malignancies in the US with peaking incidence in patients age 80 years and without relevant changes in incidence   from 2004 to 2016.A total of 43 different renal sarcoma histiotypes were reported, the most common being LMS and malignant rhabdoid tumors.Renal sarcomas manifested at a median age of 60 years, with a median diameter of 10 cm, and with metastases in 29.1% of cases, of which the majority were pulmonary.Still, considerable variability of demographic parameters and clinical presentation was evident according to the sarcomas histiotype.
Renal sarcomas seem to resemble retroperitoneal sarcomas from an epidemiological point of view: data on retroperitoneal STS diagnosed from 1973 to 2001 reported no temporal changes in incidence 15 , while analyses from the French network of cancer registries support a female LMS predominance 16 .Further, the heterogeneity of sarcoma histiotypes with varying clinical presentation is well described in the current literature, although most studies tend to focus on STS of the extremities and trunk without specific analyses for renal sarcomas 5,6,17 .
This analysis found that surgical resection was the cornerstone of renal sarcoma treatment, with almost 70% of NCDB cases receiving radical nephrectomy.Systemic therapy alone or in combination was mainly used for locally advanced renal sarcomas or patients with distant metastases, while radiation for the primary site was performed only in a minority of patients (5.2%).Although surgical resection and systemic therapy were generally associated with longer OS on multivariable analyses, their effectiveness varied according to sarcoma histiotype.These results indicate a variable sensitivity to systemic therapy according to histiotype, highlighting the importance of histiotype-specific treatment approachs for renal sarcoma, which is in line with previous observations in STS 18,19 .
Real-world renal sarcoma treatment patterns seem to follow guideline recommendations for renal cell carcinoma, advocating surgical resection with curative intent for early-stage renal cancer, and systemic therapy for metastatic disease, which can be accompanied by cytoreductive surgery in selected patients 20,21 .Although recent trials have questioned the role of cytoreductive nephrectomy in the setting of systemic therapy advances 22,23 , the NCDB data reported up to 2016 most likely does not reflect these developments.In contrast to renal cancer guidelines, the ESMO guideline on visceral and soft tissue sarcomas advocate risk-adapted perioperative treatments in sensitive histotypes, which may involve perioperative chemotherapy and/or radiation 24 .Non-superficial, www.nature.com/scientificreports/large sarcoma size (> 5 cm) and grade 2 or 3 are considered key factors to define high-risk, which render patients candidates for multimodal therapy 24 .However, among comparable renal sarcoma patients, less than 55% received systemic therapy and less than 6% radiation of the primary site, which may indicate an underutilization of multimodal therapy in these patients.
Although resection of pulmonary metastases with or without prior chemotherapy is considered standard of care according to ESMO guidelines 24 , the sole use of systemic therapy is recommended in cases with extrapulmonary metastases.In the NCDB, the majority of renal sarcoma patients with extra-pulmonary metastases were treated with surgical resection with or without systemic therapy (58.3%).
Both of these findings corroborate that real-world renal sarcoma treatment resembles that of renal cancer and not that of STS.To individualize and optimize multidisciplinary treatment planning, pre-treatment tumor biopsies may play a clinical role for renal sarcoma patients, which would follow guidelines recommending tumor biopsies for the management of retroperitoneal STS.While renal tumors with classical radiological findings often undergo upfront surgical resection, biopsies might be benefitial in patients presenting with atypical renal tumors.For example, patients with very large, heterogeneous renal tumors and infiltration of adjacent organs have a higher probability of renal sarcoma, as reported in an earlier study, and might thus benefit from a tumor biopsy 25 .
The distinction of renal sarcoma and retroperitoneal STS is a diagnostic challenge, both for radiologists and pathologsits.While some imaging markers might suggest a renal origin, such as the so-called claw-sign on cross-sectional radiological imaging 26 , large tumor diameter and perifocal tumor infiltration might complicate the diagnosis.The comparable epidemiology of renal sarcomas and retroperitoneal STS observed in this study might be further evidence that misclassifications could have occurred in the NCDB and SEER databases.In particular, the retrospective character of theses databases did not allow for a case review by reference pathologists or experienced GU-radiologists.
While this study revealed a median overall survival of 25 months for renal sarcomas, OS rates showed relevant variability according to sarcoma histiotype, as well as treatment approach (multivariable p < 0.05).Patients who received multimodal therapy, consisting of surgery and chemotherapy, achieved significant better OS, suggesting that STS guidelines might be appropriate for renal sarcoma treatment planning.
Although sarcoma grade was not available from the NCDB in the majority of cases, histological tumor necrosis was used as a surrogate parameter and emergerd as a negative independent OS predictor for renal sarcomas.
Several of the OS predictors for renal sarcomas identified in this study have been described for STS as well.For example, sarcoma histiotype, patient age, tumor extent, FNCLCC grading, as well as surgical resection margins are components of nomograms for prediction of overall survival and disease-specific death in STS patients [27][28][29] .
This study is not devoid of limitations.First, despite information on the histiotype, no details were available on the mutational status of renal sarcomas.Second, histological grading was not reported for the majority of renal sarcomas in the NCDB, although the presence of tumor necrosis may serve as a surrogate parameter.Third, the inaccuracy of histopathology in the absence of central review is well-recognized 18 .
Furthermore, no data on cancer-specific and recurrence-free survival were available from the NCDB.Since only a minority of renal sarcoma patients received radiation therapy, no conclusive analyses regarding the effectiveness of local radiation were possible in this study.Given the similarities between renal sarcomas and retroperitoneal STS observed in this study, further trials are warranted to evaluate radiation therapy protocols for patients presenting with renal sarcomas.Finally, details on systemic therapy regimens were unavailable from the NCDB, which prevented analyses of the clinical effectiveness of specific systemic therapy protocols.

Conclusions
This analysis demonstrates that renal sarcomas comprise 0.25% of all renal malignancies in the US with constant incidence rates from 2004 to 2016.Renal sarcoma histiotypes show considerable heterogeneity regarding epidemiology, clinical presentation, outcome and sensitivity to systemic therapy, and thus should be considered separate entities with individualized treatment approaches.
Although similar to retroperitoneal STS, renal sarcoma real-world treatment patterns closely resemble those recommended by renal cancer guidelines.In turn, this may indicate suboptimal utilization of multimodal therapy in selected renal sarcoma patients, which is considered the standard-of-care by visceral and soft tissue sarcoma guidelines.Given the variability of renal sarcoma therapy options and efficacy, a multidisciplinary treatment approach at specialized centers should be considered to optimize patient outcomes.
Future studies are needed to assess the efficacy of specific systemic therapy protocols in renal sarcomas, as well as to evaluate local and distant control rates.

Figure 1 .
Figure 1.Age-adjusted incidence rates of renal sarcomas by sex, provided as cases/1 million.Empty rows indicate missing cases from the SEER database.

Figure 3 .Figure 4 .
Figure 3. Representative histological cases of primary renal angiosarcoma (A), primitive neuroectodermal tumor (PNET; B) and dedifferentiated liposarcoma (C).(A) Section from a 19 cm renal angiosarcoma involving the renal cortex with entrapped glomeruli.Inset: Higher magnification (400×) demonstrating vascular spaces lined by atypical endothelial cells.(B) Core needle biopsy tissue demonstrating renal PNET with vaguely lobular growth of small round blue cells with hyperchromatic nuclei and pseudo-rossette formation (arrowheads).(C) Core needle biopsy tissue demonstrating dedifferentiated liposarcoma with pleomorphic spindle cells within a vascular and collagenous stroma.The tumor cells demonstrate cdk-4 (inset) and Rb expression by immunohistochemistry as well as mdm-2 amplification by fluorescence in situ hybridization.

Figure 5 .
Figure 5. differences in overall survival according to renal sarcoma histiotype.

Table 1 .
Baseline characteristics of included NCDB patients.

Table 2 .
Treatment variables of included NCDB patients.